1,1{40 -bridged-bis{8 n-(alkyl)-2-aminoethanols{9

ABSTRACT

1,1&#39;&#39;-Bridged-bis(N-(alkyl and/or aralkyl)-2-aminoethanols) of the formula   ARE PREPARED BY CONDENSING AN AMINE OF THE FORMULA R-CH2-NH-R&#39;&#39; with a diepoxide of the formula   The products and acidaddition salts thereof have antibacterial activity in vitro and are useful as antibacterial agents.

nited States Patent [191 Diana et al. I

1 Dec. 17, 1974 1,1 '-BRlDGED-B1S[N-(ALKYL)-2- AMINOETHANOLS] [75] Inventors: Guy D. Diana, Stephentown; Royal A. Cutler, Sand Lake, both of NY.

[73] Assignee: Sterling Drug Inc., New York, NY.

[22] Filed: Mar. 10, 1971 [21] Appl. No.: 123,096

[56]- References Cited UNITED STATES PATENTS 3,328,467 6/1967 Hamilton 260/584 R 3,555,095 l/l97l Slagel 260/584 R 1,915,334 6/1933 Salzberg et a1. 260/293.51 2,075,359 3/1937 Salzberg et a1. zen/293.51

Primary Examiner-Joseph A. Narcavage Assistant Examiner-Jose Tovar Attorney, Agent, or FirmTheodore C. Miller; B. Woodrow Wyatt [5 7] ABSTRACT 1,1 '-Bridged-bis[N-(alkyl aminoethanols] of the formula and/or aralky1)-2- are prepared by condensing an amine of the formula RCl-l -Nl-1R' with a diepoxide of the formula 0 0 5% Hi1. H.

The products and acidaddition salts thereof have antibacterial activity in vitro and are useful as antibacterial agents.

18 Claims, No Drawings 1 1,1-BRIDGED-BIS[N-(ALKYL)-2- AMINOETHANOLS] This invention relates to compositions of matter classified in the art of organic chemistry as l,l-bridgedbis[N-(alkyl and/or aralkyl)-2-aminoethanols] and to a process for preparing them.

In its composition of matter aspect our invention provides 1,1'-(X)-bis[2-[(R-Cl-l )(R)amino]ethanol] of the formula wherein:

R, when taken alone, is hydrogen, alkyl of one to fifteen carbon atoms, cycloalkyl of four to seven ring carbon atoms, phenyl or phenyl substituted by one to three members selected from the group consisting of atertiary alkyl of one to four carbon atoms, hydroxy, atertiary alkoxy of one to four carbon atoms and halo or by a member selected from the group consisting of acetamido, dimethylamino, methylthio, methylsulfonyl, nitro, trifluoromethoxy and trifluoromethyl;

R, when taken alone, is hydrogen or atertiary alkyl of one to four carbon atoms;

R and R, when taken together with CH,--N, are lpyrrolidinyl, piperidino, l-hexahydroazepinyl, morpholino or 4-methyl-l-piperazinyl;

X is a direct linkage, methylene or alkylene of two to twelve carbon atoms with bonds to the adjacent carbon atoms at different carbon atoms; and

acid-addition salts thereof.

The compounds of Formula I and acid-addition salts thereof have antibacterial activity in vitro and are use ful as antibacterial agents. i

In its process aspect our invention provides the process for preparing 1,l'-(X)-bis[2-[ (R- CH )(R')amino]ethanol] of Formula I which comprises condensing an amine of the formula R-CH -NH-R' (Formula ll) with a diepoxide of the formula (LTIzlH-X- I I-CH (Formula III),

wherein R and R of Formula II and X of Formula 111 have the same meanings ascribed thereto above in Formula I.

When R is alkyl of one to fifteen carbon atoms, it is normal alkyl or branched alkyl as illustrated by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertbutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, and pentadecyl. Since R and the attached methylene are integral, they are named integrally when R is alkyl, phenyl and substituted phenyl. Thus the illustrated alkyls become, respectively, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, Z-methybutyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and hexadecyl. When R and the attached methylene are phenyl or substituted phenyl, they are named as benzyl or substituted benzyl, respectively.

When R is phenyl substituted by atertiary alkoxy of one to four carbon atoms, atertiary alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or secbutoxy Atertiary means non-tertiary When R is phenyl substituted by halo, halo is fluoro, chloro, bromo or iodo.

When X is alkylene of two to twelve carbon atoms with bonds to the adjacent carbon atoms at different carbon atoms, it can be unbranched or branched. If unbranched, X is 1,2-ethylene, 1,3-propylene, 1,4- butylene, 1,5-pentylene, 1,6-hexylene, 1,7-heptylene, 1,8-octylene, 1,9-nonylene, 1,l0-decylene, l,l lundecylene, or 1,12-dodecylene. If branched, X is, for example, l,2-propylene, 2,3-butylene, or 2,2-dimethyl- 1 ,4-butylene. I The manner and process of making and using the in vention and the best mode of carrying it out will now be described so as to enable any person skilled in the art to which it pertains to make and use it.

The preferred method for carrying out the process of condensing an amine of Formula II with a diepoxide of Formula Ill is the use of a solvent inert under the reaction conditions, for example, acetonitrile, benzene, chloroform, N,N-dimethylformamide, ethanol, methanol or tetrahydrofuran at a temperature in the range of 0 to C. Methanol is the preferred solvent and room temperature is the preferred temperature.

Compounds of Formula I in which R is methyl are also prepared by methylating the corresponding compounds of Formula I in which R is hydrogen with formaldehyde and formic acid.

Formation of acid-addition salts of the compounds of Formula I is accomplished by standard methods with any pharmaceutically acceptable inorganic (mineral) or organic acid. If inorganic, the acid can be, for example, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid or sulfamic acid. lf organic, the acid can be, for example, acetic acid, glycolic acid, lactic acid, quinic acid, hydrocinnamic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid or benzenesulfonic acid.

That the acid be pharmaceutically acceptable means that the beneficial properties inherent in the free base not be vitiated by side effects ascribable to the anions.

Although pharmaceutically acceptable salts are preferred, all acid-addition salts are within the scope of the invention. A pharmaceutically unacceptable salt may be useful, for example, for purposes of identification or purification or in preparing a pharmaceutically acceptable salt by ion-exchange procedures.

The intermediate amines of Formula ll are a known class of compounds, whose preparation is accomplished by any of several well-known methods. The amines in which R is hydrogen, alkyl or cycloalkyl can be prepared, for example, by reductive amination of the corresponding aldehyde, by amination of the corresponding halide or alcohol p-toluenesulfonate ester or by reduction of the corresponding nitrile, oxime, amide, azide or other highenoxidation-state nitrogen compound. The amines in which R is phenyl or substitutedphenyl can be prepared, for example, by brominating the corresponding toluene, treating the resulting a-bromotoluene with hexamethylenetetramine and treating the resulting product successively with sulfur dioxide hydrochloric acid and ammonia; by reductive amination of the corresponding aldehyde or by reduction of the corresponding nitrile, oxime, amide or other higher-oxidation-state nitrogen compound.

The intermediate diepoxides of Formula III are also a known class of compounds. Their preparation is accomplished by epoxidation of the corresponding dienes by any of several well-known methods, for example, by the use of peracetic acid buffered with sodium acetate.

The compounds of Formula I and acid-addition salts thereof are purified by recrystallization. Their structures follow from their route of synthesis and are corroborated by infrared spectral analysis and by the correspondence of calculated and found values of elemental analysis of representative samples.

As stated above the compounds of Formula I have antibacterial activity in vitro, which was determined by a standard serial dilution test. In this test the concentration of compound arresting the growth of the microorganism is the bacteriostatic concentration and is expressed in parts per million (p.p.m.). The concentration of compound preventing growth of the microorganism after further incubation is the bactericidal concentration and is also expressed in parts per million.

The compounds of Formula I and acid-addition salts thereof are useful as antibacterial agents and are especially useful for disinfecting and sanitizing living and non-living surfaces by conventional swabbing, padding, spraying, immersing, rinsing and the like techniques. Depending on the particular purpose involved, the compounds are used in aqueous solution, in aqueous detergent solutions or in solutions in organic solvents.

The following examples illustrate specific embodiments of our invention without limiting the latter thereto.

EXAMPLE 1 A solution of nonylamine (44.4 g.), l,2;7,8- diepoxyoctane g.) and methanol (125 ml.) was allowed to stand at room temperature (for 1 hr.), cooled in the refrigerator (for 2 hr.), then allowed to stand at room temperature overnight. Recrystallization of the resulting product (46 g.) from methanol afforded 1,1- (l,4-butylene)-bis[2-(nonylamino)ethanol] (I: R CH (CH R H, X (CH (10.8 g., m.p. 122.6-l28.8C.).

Table I shows the results of the antibacterial testing in vitro of 1,1 1,4-butylene)-bis-[2- (nonylamino)ethanol].

EXAMPLE 3 Condensation of ethylamine and 1,2;7,8- diepoxyoctane affords 1,1 1,4-butylene )-bis[ 2- (ethylamino)ethanol] (I: R CH R H, X 2)4)' EXAMPLE 4 Condensation of propylamine and 1,2;7,8- diepoxyoctane affords 1,1'-(l,4-butylene)-bis[2- (propylamino)ethanol] (I: R CH CH R H, X OU EXAMPLE 5 Condensation of butylamine and l,2;7,8- diepoxyoctane affords 1,1 l ,4-butylene)-bis[ 2- (butylamino)ethanol] (I: R CH (CH R H, X 94)- EXAMPLE 6 Condensation of isobutylamine and l,2;7,8- diepoxyoctane affords 1,1 1,4-butylene )-bis[ 2- (isobutylamino)ethanol] (l: R (CH CH, R H, X 2)4)- EXAMPLE? Condensation of pentylamine and l,2;7,8- diepoxyoctane affords 1,1'-(l,4-butylene)-bis[2- (pentylamino)ethanol] (I: R CH (CH R H, X -2h) EXAMPLE 8 Condensation of isopentylamine and l,2;7,8- diepoxyoctane affords 1,1 l ,4-butylene)-bis[2- (isopentylamino)ethanol] (l: R (CH CHCH R H, X 2)4)- EXAMPLE 9 Condensation of 2-methylbutylamine and l,2;7,8- diepoxyoctane affords 1,1 1,4-butylene )-bis[2-( 2- methylbutylamino)ethanol] (I: R CH CI-I (CH )CH, H, X (C AO- EXAMPLE 1O In a manner similar to that of Example 1, condensation of hexylamine (14.3 g.) and l,2;7,8-diepoxyoctane (10 g.) and recrystallization of the resulting product from methanol gave 1,1 l ,4-buty1ene)-bis[2- Table I Microorganism Bacteriostatic Bactericidal concentration (p.p.m.) concentration (p.p.m.)

Staphylococcus aureus 2.5 25 Eberlhella lyphi 5 7.5 Closrridium welchii 5 5 Pseudomonas aeruginom 25 25 EXAMPLE 2 (hexylamino)ethanol] (I: R =CH (CH R H, X

Condensation of methylamine and 1,2;7,8- (Cl-12)) (10 4280 diepoxyoctane affords 1,1 '-(1,4-butylene)-bis[2- (methylamino)ethanol] (I: R H, R H, X EXAMPLE 12 (CH Condensation of heptylamine and l,2',7,8-

diepoxyoctane affords 1,1 1,4-butylene)-bis[2- EXAMPLE 21 I (heptylammokthanou (I: R CH3(CH2)5 RI X Condensation of (cyclobutylmethyl)amine and (CH2)4)' 1,2;7,8-diepoxyoctane affords EXAMPLE 13 l,l'-(1,4-butylene)-bis[2-[(cyclobutylmethyl)- 5 amino]ethanol] In a manner similar to that of Example 1, condensation of octylamine (36.6 g.) and l,2;7,8-diepoxyoctane v (20 g.) and recrystallization of the resulting product Q S E :)O- (30 g.) from methanol gave 1,1-(1,4-butylene)-bis[2- (octylamino)ethanol] (l: R CH (CH R H, X 10 EXAMPLE 22 (Cl-m) 1250 Condensation of (cyclopentylmethyl)amine and EXAMPLE 14 1,2;7,8-diepoxyoctane affords 1 ,1 l ,4-butylene)-bis[ 2-[ (cyclopentylmethyl- In a manner similar to that of Example 1, condensa- 15 )am1no]ethanol] tion of decylamine (69.92 g.) and l,2;7,8- diepoxyoctane (28.4 g.) and recrystallization of the resulting product (48 g.) from methanol gave 1,l'-(1,4-

' c ":Q""" butylene)-bis[2-(decylamino)ethanol] (I: R (L W CH3(CH2)8, R H, x 01 34.9 g., m.p. 2O

l07.8-126.6C.) EXAMPLE 23 EXAMPLE 15 Condensation of (cyclohexylmethyl)amine and 1 ,2;7,8-diepoxyoctane affords Condensation of undecylamine and 1,2; 7,8-

1, ,4- L -J diepoxyoctane affords 1,1'-(l;4-butylene)-bis[2- 25 g gfi h (undecylamino)ethanol] (l: R CH (CH R H, X

= i 7 77. V.... .r. z W

Condensation of dodecylamine and l,2;'7,8- 3O diepoxyoctane affords -1,1-( l,4-butylene)-bis[2- EXAMPLE 24 (dodecylaminolethanoll R CHACHZM Condensation of (cycloheptylmethyl)amine and X z)4)- l,2;7,8-diepoxyoctane I affords I EXAMPLE 17 1,1'-(1,4-butylene)-bis[2-[(cycloheptylmethyl)- y l amino]ethanol] Condensation of tridecylamme and l,2;7,8-

diepoxyoctane affords 1,1 l,4-butylene)-bis[2- (tridecylamino)ethanol] (I. R CH (CH R H, ii"fi'="cm(cfiiikofi. =(t1 1 t;);) X (CH2)4)- I EXAMPLE l8 EXAMPLE 25 Condensation of tetra yl min n In a manner similar to that of Example 1, condensadiepoxy'oc ane affords y tion of 3,4-dichlorobenzylamine (75.4 g.) and 1,2;7,8- (tetradecylamino)ethanol] a( z)12 diepoxyoctane (30.4 g.) and two recrystallizations of X (CH2)4- .the resulting product from ethanol gave 1,1'-,(1,4-

' butylene)-bis[2-(3,4'-dichlorobenzylamino)-ethanol] EXAMPLE (1: R 3,4-Cl C H R H, x cam 20 g., m.p. Condensation of pentadecylamine and l,2;7,8- 14l.0-l50.0C.).

diepoxyoctane affords 1,1 l,4-butylene)-bis[2- Table 11 shows the results of the antibacterial testing (pentadecylamino)ethanol] (I: R CH (CH R in vitro of 1,1'-(1,4-butylene)-bis[2-(3,4- X 2h)- dichlorobenzylamino)ethanol].

Table 11 Microorganism Bacteriostatic Bactericidal concentration (p.p.m.) concentration (p.p.m.)

Staph lococcus aureus 7.5 100 Ebert Ila ryphi 25 50 Closm'dium welchii 7.5 7.5 Pseudomanas aemginma EXAMPLE 20 EXAMPLE 26 Condensation of hexad ylamin and 3- In a manner similar to that of Example 1, condensadiepoxyoctane affords 1,l'-(l,4- uty is[2- 65 tion of benzylamine (31 g.) and l,2;7,8-diepoxyoctane ad y m nm a l( a(CHz)u. (20 g.) and recrystallization of the resulting product X =(CH from acetone gave 1,1'-(l,4-butylene)-bis-[2-' (benzylamino)ethanol] (1: R C H R H, X (CH (4.3 g. m.p. 107.0117.0C.).

EXAMPLE 27 Condensation of o-methylbenzylamine and 1,2;7,8- diepoxyoctane affords 1,1 1,4-butylene)-bis[2-(omethylbenzylamino)-ethanol] (I: R oCH C H R X 2)4)' EXAMPLE 28 Condensation of p-hydroxybenzylamine and 1,2;7,8- diepoxyoctane affords 1,1 1,4-butylene)-bis[2-(phydroxybenzylamino)-ethanol] (I: R pHOC H R X QO' EXAMPLE 29 Condensation of m-methoxybenzylamine and l,2;7,8-diepoxyoctane affords 1,1 1 ,4-butylene)- bis[2-(m-methoxybenzylamino)-ethanol] (l: R mCH OC H R H, X

EXAMPLE 30 1n a manner similar to that of Example 1, condensation of o-chlorobenzylamine (100 g.) and l,2;7,8- diepoxyoctane (50 g.) and recrystallization of the resulting product first from acetone and then twice from isopropyl alcohol gave 1,1'-(1,4-butylene)-bis[2-(ochlorobenzylamino)ethanol] (l: R =o-ClC H R H, X (CH (10.8 g., m.p. l35.0-l38.8C.).

EXAMPLE 31 In a manner similar to that of Example 1, condensation of p-chlorobenzylamine (100 g.) and 1,2;7,8- diepoxyoctane (50 g.) and recrystallization of the resulting product first from acetone and then twice from isopropyl alcohol gave 1,l'-(1,4-butylene)-bis[2-(pchlorobenzylamino)ethanol] (1: R pC1C H R H, X (CH (9.4 g., m.p. l28.013l.0C.).

EXAMPLE 32 Condensation of p-fluorobenzylamine and l,2;7,8- diepoxyoctane affords 1,1'-(l,4-butylene)-bis[2-(pfluorobenzylamino)ethanol] (l: R pFC H R H, X 04)- EXAMPLE 33 Condensation of p-bromobenzylamine and 1,2;7,8-

diepoxyoctane affords 1,1-(1,4-butylene)-bis[2-(pbromobenzylamino)ethanol] (I: R pBrC H R H, x (CH2)4)- EXAMPLE 34 Condensation of p-iodobenzylamine and 1,2;7,8- diepoxyoctane affords 1,1 1,4-butylene )-bis[2-(piodobenzylamino)ethanol[ (I: R plC H R= H, X 2)4)- EXAMPLE 35 EXAMPLE 36 of o-acetamidobenzylamine and affords 1,1 l,4-butylene)- Condensation 1 ,2;7,8-diepoxyoctane bis[ 2-(o-acetamidobenzylamino )ethanol] EXAMPLE 37 Condensation of p-(dimethylamino)benzylamine and l,2;7,8-diepoxyoctane affords 1,1-( 1 ,4-butylene)- bis[2-[p-(dimethylamino)-benzylamino]ethanol] (1: R P'( a)2 s 4, H, X 2)4)- EXAMPLE 38 Condensation of p-(methylthio)benzylamine and 1,2;7,8-diepoxyoctane affords 1,1'-(l,4-butylene)- bis[2-[p-(methylthio)-benzylamino]ethanol] (I: R pCH SC H R H, X (CH EXAMPLE 39 Condensation of p-(methylsulfonyl)benzylamine and 1,2;7,8-diepoxyoctane affords l,1'-(1,4-butylene)- bis[Z-[p-(methysulfonyl)-benzylamino]ethanol] (l: R PCH3SOZCQH4, R H, X

EXAMPLE 40 EXAMPLE 41 Condensation of p-(trifluoromethoxy)benzylamine and 1,2;7,8-diepoxyoctane affords l,l(l,4-butylene)- bis[Z-[p-(trifluoromethoxy)benzylamino]ethanol] (l:

EXAMPLE 42 Condensation of p-(trifluoromethyl)benaylamine and l,2;7,8-diepoxyoctane affords l,l-(l,4-butylene)- EXAMPLE 43 A. 1,1 1,4-Butylene )-bis[2-(nonylamino )ethanol] (16 g.) was added in portions to a solution of formic acid (98-l00%, 16 ml.) and formaldehyde (38%, 10 ml.) held at C. When the addition was complete the resulting solution was refluxed (for 9 hr.), then basified with sodium hydroxide solution (35%). The resulting mixture was extracted with ether and the ethereal extract was shaken without methanolic potassium hydroxide. Addition of water and separation, desiccation and evaporation of the ether layer afforded a colorless oil (13 g.). Treatment of an ethereal solution of the oil with ethereal hydrogen bromide (0.8 N, ml.) and recrystallization of the resulting solid from acetonitrile gave 1,1-(l,4-butylene)-bis[2- (methylnonylamino)ethanol] (l: R CH (CH R CH X (CH2)4) dihydrobromide (10.5 g.. m.p. 148.0-15 10C.).

Table 111 shows the results of the antibacterial testing in vitro of l,1'-(1,4-butylene)-bis[2- (methylnonylamino)-ethanol] dihydrobromide.

Table III Microorganism Bacteriostatic Bactericidal concentration (p.p.m.) concentration (p.p.m.)

Staphylococcus aureus 5 25 Elberthella typhi 25 25 Clostridium welchii 7.5 7.5

Pseudomonas aeruginosa I00 100 B. Condensation of methylnonylamine and l,2;7,8- EXAMPLE 47 diepoxyoctane and treatment of the resulting product with hydrogen bromide also affords 1,1 '-(1, 4- butylene)-bis[2-(methylnonylamino)ethanol] dihydrobromide.

C. Using hydrochloric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, glycolic acid, lactic acid, quinic acid, hydrocinnamic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid and benzenesulfonic acid instead of hydrobromic acid ,in Part A of this Example, there are obtained, respectively,

1 ,1 1,4-butylene )-bis[2- (methylnonylamino)ethanol] dihydrochloride,

1,1-(l,4-butylene)-bis[2- (methylnonylamino)ethanol] dinitrate,

l,l l,4-butylene )-bis[ 2- (methylnonylamino)ethanol] diphosphate,

1,1 l,4-butylene)-bis[2- (methylnonylamino)ethanol] disulfamate,

1,1 1,4-butylene )-bis[ 2- (methylnonylamino)ethanol] diacetate,

1,1 l,4-butylene)-bis[2- (methylnonylamino)ethanol] diglycolate,

l,l l-,4-butylene)-bis[2- (methylnonylamino)ethanol] dilactate,

l,l l,4'butylene)-bis[2- (methylnonylamino)ethanol] diquinate,

l ,1 l ,4-butylene)-bis[2- (methylnonylamino)ethanol1 dihydrocinnamate,

1,1'-(l,4-butylene)bis[2- (methylnonylamino)ethanol] succinate,

l,l'-( l,4-butylene)-bis[ 2- (methylnonylamino)ethanol1 tartrate,

l,l l,4-butylene)-bis[2- (methylnonylamino)ethanol] dicitrate,

(methylnonylamino)ethanol] dimethanesulfonate,

and 1,1 l,4-butylene)-bis[ 2- (methylnonylamino)ethanol] dibenzenesulfonate.

EXAMPLE 44 Condensation of ethylnonylamine and l,2;7,8- diepoxyoctane affords l,l l,4-butylene )-bis[2- (ethylnonylamino)ethanol] (I: R Cl-l0hd CH R 3 2, X 2)4)- EXAMPLE 45 Condensation of propylnonylamine and l,2;7,8-

diepoxyoctane affords 1,1 1,4-butylene )-bis[ 2- (propylnonylamino)ethanol1 (l: R CH (CH R EXAMPLE 46 Condensation of butylnonylamine and l,2;7,8- diepoxyoctane affords l,l 1,4-butylene )bis[2- (butylnonylamino)ethanol] (I: R CH (CH R a( 2)3, X H2)4)- EXAMPLE 48 Condensation of isobutylnonylamine and l,2;7,8- diepoxyoctane affords l ,l l ,4-butylene )-bis[2- (isobutylnonylamino)ethanol] (l: R CH (Cl-l R ah m x 2)4) EXAMPLE 49 Condensation of sec-butylnonylamine and l,2;7,8

diepoxyoctane affords 1,1 1 ,4-butylene)-bis[2-(secbutylnonylamino)ethanol] (l: R CH (CH R CH CI'I a) X 2)4)- EXAMPLE 50 In a manner similar to that of Example 43, methylation of 1,1 1 ,4-butylene)-bis[2- (hexylamino)ethanol] (15 g.), treatment of the result ing product with hydrogen bromide and recrystallization of the resulting salt from acetonitrile gave 1,1- l,4-butylene)-bis[2-(methylhexylamino)ethanol] (l:

R CH3(CH2)4, R CH3, X dlhydrobromide (8.8 g., m.p. l23.0l27.8C.).

EXAMPLE 51 EXAMPLE 52 In a manner similar to that of Example 43, methylation of Li '-(l,4-butylene)-bis[2-(octylamino)ethanol] (25 g.), treatment of the resulting product with hydrogen bromide and recrystallization of the resulting salt from acetonitrile gave 1,1 l,4-butylene)-bis-[2- (methyloctylamino)ethanol] (l: R CH CH R CH X (CH dihydrobromide (13.8 g., m.p. l43.0-l44.8C.).

EXAMPLE 53 In a manner similar to that of Example 43, methylation of l,1-( 1,4-butylene )-bis[ 2- (decylamino)ethanol] (20 g.), treatment of the resulting product with hydrogen bromide and two recrystallization of the resulting salt from acetonitrile gave 1,1 l ,4-butylene )-bis-[2-(methyldecylamino)ethanol] (l: R CH (CH R CH;,, X (Cl-M dihydrobromide (8.1 g., m.p. l48.0150.6C.).

EXAMPLE 54 In a manner similar to that of Example 43, methylation of 1,1'-(1,4-butylene)-bis[2-(3,4- dichlorobenzylamino)ethanol] (13 g.) and recrystallization of the resulting product from methanol gave 1,1- 1,4-butylene)-bis[2-( 3,4-dichlorobenzylmethylamino)ethanol] (l: R 3,4-Cl C H R CH X (CH (4.9 g., m.p. l14.6117.0C.)

Table IV shows the results of the antibacterial testing in vitro of 1,1'-(1,4-butylene)-bis[2-(3,4- dichlorobenzylmethylamino) ethanol].

EXAMPLE 59 Condensation of l-methylpiperazine and l,2;7,8- diepoxyoctane affords 1,1 l,4-butylene)-bis[2-( 4- methyl- 1 -piperazinyl) ethanol] 1,l l ,4-butylene)-bis[2-( l-pyrrolidinyl)ethanol] In a manner similar to that of Example 1, condensation of dodecylamine (40.4 g.) and 1,2;3,4- diepoxybutane (9.4 g.) and recrystallization of the resulting product from ethanol gave 1,1 -bis[2- EXAMPLE 56 30 (dodecylamino)ethanol] (l: R cu wnn R H, Condensation of piperidine and l,2;7,8- X a direct linkage) (13.4 g., m.p. l25.0-133.8C.). diepoxyoctane affords Table V shows the results of the antibacterial testing 1,1 l ,4-butylene)-bis[Z-piperidinoethanol] in vitro of 1,1'-bis[2-(dodecylamino)ethanol].

Table V Microorganism Bacteriostatic Bactericidal concentration (p.p.m.) concentration (p.p.m.)

Staph lococcus aureus 50 50 Ebert Ila lyphi 2s 7s Closlridium welchii 50 50 Pseudomonas aeruginosa 100 EXAMPLE 61 R CHZ I I=CHZ(CH)N' X=(CH)4 Condensation of undecylamine and 1,2;4,5-

EXAMPLE 57 Condensation of hexahydroazepine and l,2;7,8- diepoxyoctane affords 1.1 l ,4-butylene)-bis[2-( l-hexahydroazepinyl)ethanol] EXAMPLE 58 In a manner similar to that of Example 1, condensation of morpholine (12.2 g.) and l,2;7,8-diepoxyoctane (10 g.) and recrystallization of the resulting product from methanol gave 1,1 l ,4-butylene)-bis[2-morpholinoethanoll diepoxypentane affords, 1,1 -methylenebis[2- (undecylamino)ethanol] (l: R =CH (CH R H, X CH2). 0

EXAMPLE 62 Condensation of decylamine and l,2;5,6-

diepoxyhexane affords 1,1 '-ethylenebis[ 2- (decylamino)ethanol] (l: R CH (CH)u. R H, X M)- EXAMPLE 63 Condensation of nonylamine and l,2;6,7- diepoxyheptane affords 1,1 1.3-propylene )-bis[2- (nonylamino)ethanol] (l: R =CH (CH R H, X 2h)- EXAMPLE 64 Condensation of octylamine and 1,2;8,9- diepoxynonane affords 1,1 l,5-pentylene)-bis[2- (octylamino)ethanol] (l: R CH (CH,) R H, X 2h)- EXAMPLE 65 Condensation of heptylamine and l,2;9,ldiepoxydecane affords, 1,1 1,6-hexylene)-bis[2- (heptylamino)ethanol] (l: R CH (CH R H, X (CH2)6)* EXAMPLE 66 Condensation of hexylamine and 1,2;10,l ldiepoxyundecane affords 1,1 l,7-heptylene)-bis[2-- (hexylamino)ethanol] (I: R CH (CH R H, X -M1)- EXAMPLE 67 Condensation of pentylamine and 1,2;11,12-

'diepoxydodecane affords 1,1-(1,8-octylene)-bis[2- (pentylamino)ethanol] (I: R Ch (CH R H, X 2)s)- EXAMPLE 68 Condensation of butylamine and 1,2;l2,l3-diepoxytridecane affords l ,1 l ,9-nonylene)-bis[2- (butylamino)ethanol] (l: R CH (CH R H, X -M9)- EXAMPLE 69 Condensation of propylamine and 1,2;1 3,14-diepoxytetradecane affords 1,1'-( 1 1 0decylene)-bis[2- (propylamino)ethanol] (I: R CH CH R H, X 910)- (octyalmino)ethanol] (1: R CH (CH R H, X CH(CH )CH(CH EXAMPLE 74 Condensation of octylamine and 1,2;7,8-diepoxy- 4,4-dimethyloctane affords 1,1 2,2-dimethyl- 1 ,4- butylene)-bis[2-(octylamino)ethanol] (I: R CH (CH R H, X CH C(CH CH CH We claim:

1. 1,1'-(X)-bis[2-[(R-CH )(R')amino]ethano1] of the formula R is hydrogen, alkyl of one to carbon atoms or cycloalkyl of four to seven ring carbon atoms;

R is hydrogen or atertiary alkyl of one to four carbon atoms;

X is a direct linkage, methylene or alkylene of two to 12 carbon atoms with bonds to the adjacent carbon atoms at different carbon atoms; or

acid-addition salts thereof.

wherein:

R is hydrogen or alkyl of one to 15 carbon atoms;

R is hydrogen or atertiary alkyl of one to four carbon atoms;

X is a direct linkage, methylene or alkylene of two to 12 carbon atoms with bonds to the adjacent carbon atoms at different carbon atoms; or

acid-addition salts thereof.

CH )(R)amino]ethanol]wherein:

R is alkyl of one to 15 carbon atoms;

R is hydrogen;

X is alkylene of two to 12 carbon atoms with bonds to the adjacent carbon atoms at different carbon atoms; or

acid-addition salts thereof according to claim 2.

wherein:

R is alkyl of one to 15 carbon atoms; R is hydrogen; X is (l,4-butylene); or acid-addition salts thereof according to claim 3. 5. 1,1 l,4-Butylene)-bis[2-(nonlyamino)ethanol] according to claim 4.

6. 1,1-( l ,4-Butylene)-bis[2-(hexylamino)ethanol] according to claim 4.

7. 1,1'-( 1,4-Butylene )-bis[2-(octylamino)ethanol] according to claim 4.

8. 1,1-(l,4-Butylene)-bis[2-(decylamino)ethanol] according to claim 4.

wherein:

R is alkyl of one to 15 carbon atoms;

R is atertiary alkyl of one to four carbon atoms;

X is alkylene of two to 12 carbon atoms with bonds to the adjacent carbon atoms at different carbon atoms; or

acid-addition salts thereof according to claim 2.

l0. 1,1'-(X)-bis[2-[(R-CH (R)amino]ethanol] wherein:

R is alkyl of one to 15 carbon atoms;

R is methyl;

X is (l,4-butylene); or

acid-addition salts thereof according to claim 9.

1 l. 1,1(-1,4-Butylene)-bis[2-(methylnonylamino)- ethanol] dihydrobromide according to claim 10.

12. 1,1 1,4-Butylene-bis[2-(methylhexylamino)ethanol] dihydrobromide according to claim 10.

13. 1,1 1,4-Butylene)-bis[2-(methylheptylamino)ethanol] dihydrobromide according to claim 10.

14. (methyloctylamido)ethanol] ing to claim l0.

l5. 1,1-(1,4-Butylene-bis[2- (methyldecylamino)ethanol] dihydrobromide according to claim 10.

16. l,1'-(X)-bis[2-[(R-CH )(R')amino]ethanol] wherein:

R is alkyl of one to 15 carbon atoms;

R is hydrogen or atertiary alkyl of one to four carbon atoms;

X is a direct linkage; or

acid-addition salts thereof according to claim 2.

l7. 1,1'-(X)-bis[2-[(R-CH )(R')amino]ethanol] wherein:

R is alkyl of one to 15 carbon atoms;

R is hydrogen;

X is a direct linkage; or

acid-addition salts thereof according to claim l6.

l8. 1,1-Bis[2-(dodecylamino)ethanol] according to claim 17.

,1 l,4-Butylene)-bis[2- dihydrobromide accord- UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 55, 97 Dated I December 17, 1974 Inventor(s) Guy D. Diana and Royal A. Cutler It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column A, line 4 "(I= ==(CH cH n R'H, x=( H should read --(I:R=(CH5)2CHCH2, R'=H, x30

Column 8, line 9 "R'H, x=(cH should read --R'=H, X=(CH2)L' )0 o Column 8, line 55 "was shaken without methanolic potassium hydroxide. should read --was shaken with methanolic potassium hydroxide.--.

R'=CH CH Column 9, lines 51L 8: 55 "(I:R=CHOhd CH( 3 X=(cH should read (I:R=CH3(CH2)7, R'=CH3CH2, X=(CH a Column 10, line 56 (I:R=CH5CH2)6R'=" should read (I:R==CH3(CH2)6R'=-- 1 Column 11, line 26 "(I:R-CH2-N=CH2(CH2)5N, X=(CH h 1d d I:R-CH i=0 CH N x= CH *sou rea 2 24 Column 12, line 40 "Pseudomonas aeruginosa 100" should read --Pseud0monas aeruginosa 100--.

Signed and Scaled this Fifteenth Day Of November 1977 [SEAL] Attest:

RUTH C. MASON LUTRELLE F. PARKER Attesting Officer Acting Commissioner of Patents and Trademarks 

1. 1,1''-(X)-BIS(2-((R-CH2)(R'')AMINO)ETHANOL) OF THE FORMULA
 2. 1,1''-(X)-bis(2-((R-CH2)(R'' )amino)ethanol) wherein: R is hydrogen or alkyl of one to 15 carbon atoms; R'' is hydrogen or atertiary alkyl of one to four carbon atoms; X is a direct linkage, methylene or alkylene of two to 12 carbon atoms with bonds to the adjacent carbon atoms at different carbon atoms; or acid-addition salts thereof.
 3. 1,1''-(X)-bis(2-((R-CH2)(R'')amino)ethanol)wherein: R is alkyl of one to 15 carbon atoms; R'' is hydrogen; X is alkylene of two to 12 carbon atoms with bonds to the adjacent carbon atoms at different carbon atoms; or acid-addition salts thereof according to claim
 2. 4. 1,1''-(X)-bis(2-((R-CH2)(R'')amino)ethanol) wherein: R is alkyl of one to 15 carbon atoms; R'' is hydrogen; X is (1,4-butylene); or acid-addition salts thereof according to claim
 3. 5. 1,1''-(1,4-Butylene)-bis(2-(nonlyamino)ethanol) according to claim
 4. 6. 1,1''-(1,4-Butylene)-bis( 2-(hexylamino)ethanol) according to claim
 4. 7. 1,1''-(1,4-Butylene)-bis(2-(octylamino)ethanol) according to claim
 4. 8. 1,1''-(1,4-Butylene)-bis(2-(decylamino)ethanol) according to claim
 4. 9. 1,1''-(X)-bis(2-((R-CH2)(R'')amino)ethanol) wherein: R is alkyl of one to 15 carbon atoms; R'' is atertiary alkyl of one to four carbon atoms; X is alkylene of two to 12 carbon atoms with bonds to the adjacent carbon atoms at different carbon atoms; or acid-addition salts thereof accordIng to claim
 2. 10. 1,1''-(X)-bis(2-((R-CH2) (R'')amino)ethanol) wherein: R is alkyl of one to 15 carbon atoms; R'' is methyl; X is (1,4-butylene); or acid-addition salts thereof according to claim
 9. 11. 1,1''(-1,4-Butylene)-bis(2-(methylnonylamino)-ethanol) dihydrobromide according to claim
 10. 12. 1,1''-(1,4-Butylene-bis(2-(methylhexylamino)ethanol) dihydrobromide according to claim
 10. 13. 1,1''-(1,4-Butylene)-bis(2-(methylheptylamino)ethanol) dihydrobromide according to claim
 10. 14. 1,1''-(1,4-Butylene)-bis(2-(methyloctylamido)ethanol) dihydrobromide according to claim
 10. 15. 1,1''-(1,4-Butylene-bis(2-(methyldecylamino)ethanol) dihydrobromide according to claim
 10. 16. 1,1''-(X)-bis(2-((R-CH2)(R'')amino)ethanol) wherein: R is alkyl of one to 15 carbon atoms; R'' is hydrogen or atertiary alkyl of one to four carbon atoms; X is a direct linkage; or acid-addition salts thereof according to claim
 2. 17. 1,1''-(X)-bis(2-((R-CH2)(R'')amino)ethanol) wherein: R is alkyl of one to 15 carbon atoms; R'' is hydrogen; X is a direct linkage; or acid-addition salts thereof according to claim
 16. 18. 1,1''-Bis(2-(dodecylamino)ethanol) according to claim
 17. 